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Pancreatic cancer—a tumor displaying a particularly abun-dant stromal reaction—is notorious for its poor prognosis. Recent studies, via newly developed orthotopic models, provide compelling evidence of an important role for pancreatic stellate cells (PSC) in pancreatic cancer progres-sion. Characterization of the mechanisms mediating PSC-cancer interactions will lead to the development of much needed alternative therapeutic approaches to improve disease outcome. [Cancer Res 2008;68(19):7707–10